Benzofuranyl Alkanamine Derivatives and Uses Thereof

ABSTRACT

Compounds of formula I or pharmaceutically acceptable salts thereof are provided: 
     
       
         
         
             
             
         
       
     
     wherein each of R 1 , R 1′ , R 2 , R 3 , R 4 , n, and Ar are as defined, and described in classes and subclasses herein, which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/674,129, filed Apr. 22, 2005, the entirety of which ishereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to 5-HT_(2C) receptor agonists, processesfor their preparation, and uses thereof.

BACKGROUND OF THE INVENTION

Schizophrenia affects approximately 5 million people. The most prevalenttreatments for schizophrenia are currently the ‘atypical’antipsychotics, which combine dopamine (D₂) and serotonin (5-HT_(2A))receptor antagonism. Despite the reported improvements in efficacy andside-effect liability of atypical antipsychotics relative to typicalantipsychotics, these compounds do not appear to adequately treat allthe symptoms of schizophrenia and are accompanied by problematic sideeffects, such as weight gain (Allison, D. B., et. al., Am. J.Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin.Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences.Decision Resources. 2:1-9, 2000).

Atypical antipsychotics also bind with high affinity to 5-HT_(2C)receptors and function as 5-HT_(2C) receptor antagonists or inverseagonists. Weight gain is a problematic side effect associated withatypical antipsychotics such as clozapine and olanzapine, and it hasbeen suggested that 5-HT_(2C) antagonism is responsible for theincreased weight gain. Conversely, stimulation of the 5-HT_(2C) receptoris known to result in decreased food intake and body weight (Walsh et.al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., HumanPsychopharmacology 10: 385-391, 1995; Rosenzweig-Lipson, S., et. al.,ASPET abstract, 2000).

Several lines of evidence support a role for 5-HT_(2C) receptor agonismor partial agonism as a treatment for schizophrenia. Studies suggestthat 5-HT_(2C) antagonists increase synaptic levels of dopamine and maybe effective in animal models of Parkinson's disease (Di Matteo, V., et.al., Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al.,Experimental Neurology 151: 35-49, 1998). Since the positive symptoms ofschizophrenia are associated with increased levels of dopamine,compounds with actions opposite to those of 5-HT_(2C) antagonists, suchas 5-HT_(2C) agonists and partial agonists, should reduce levels ofsynaptic dopamine. Recent studies have demonstrated that 5-HT_(2C)agonists decrease levels of dopamine in the prefrontal cortex andnucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37:953-955, 1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195-1205,1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regionsthat are thought to mediate critical antipsychotic effects of drugs likeclozapine. However, 5-HT_(2C) agonists do not decrease dopamine levelsin the striatum, the brain region most closely associated withextrapyramidal side effects. In addition, a recent study demonstratesthat 5-HT_(2C) agonists decrease firing in the ventral tegmental area(VTA), but not in the substantia nigra. The differential effects of5-HT_(2C) agonists in the mesolimbic pathway relative to thenigrostriatal pathway suggest that 5-HT_(2C) agonists have limbicselectivity, and will be less likely to produce extrapyramidal sideeffects associated with typical antipsychotics.

SUMMARY OF THE INVENTION

The present invention relates to 5-HT_(2C) agonists and uses thereof. Inone aspect, the invention relates to novel7-aryl-(1-benzofuran-2-yl)alkanamine derivatives that act as agonists orpartial agonists of the 5-HT_(2C) receptor. The compounds are useful,for example, to treat schizophrenia and the concomitant mood disordersand cognitive impairments of schizophrenia. In certain embodiments,compounds of the present invention are less likely to produce the bodyweight increases associated with current atypical antipsychotics. Thecompounds of the present invention are also useful for the treatment ofobesity and its comorbidities.

In certain embodiments, the present invention provides a compound offormula I:

or pharmaceutically acceptable salts thereof, wherein:

-   each of R¹ and R^(1′) is independently hydrogen, methyl, ethyl,    2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl;-   each of R², R³ and R⁴ is independently hydrogen, halogen, OH, lower    alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN;-   Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally    substituted with one or more R^(x) groups;    each R^(x) is independently halogen, —OH, —CN, lower alkyl, lower    alkoxy, —CF₃, or —OCF₃; and    n is one or two.

In certain other embodiments, the invention relates to methods fortreating a patient suffering from schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder,substance-induced psychotic disorder, L-DOPA-induced psychosis,psychosis associated with Alzheimer's dementia, psychosis associatedwith Parkinson's disease, psychosis associated with Lewy body disease,dementia, memory deficit, intellectual deficit associated withAlzheimer's disease, bipolar disorders, depressive disorders, moodepisodes, anxiety disorders, adjustment disorders, eating disorders,epilepsy, sleep disorders, migraines, sexual dysfunction, substanceabuse, addiction to alcohol and various other drugs, including cocaineand nicotine, gastrointestinal disorders, obesity, or a central nervoussystem deficiency associated with trauma, stroke, or spinal cord injurythat includes administering to the patient a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof.

In still other embodiments, the invention relates to compositionscomprising a compound of formula I or a pharmaceutically acceptable saltthereof, and one or more pharmaceutically acceptable carriers,excipients, or diluents.

DETAILED DESCRIPTION OF THE INVENTION 1. Compounds and Definitions

The present invention relates to novel7-[aryl]-(1-benzofuran-2-yl)alkanamine derivatives that are agonists orpartial agonists of the 2C subtype of brain serotonin receptors.

The term “lower alkyl,” as used herein, refers to a hydrocarbon chainhaving up to 4 carbon atoms, preferably 1 to 3 carbon atoms, and morepreferably 1 to 2 carbon atoms. The term “alkyl” includes, but is notlimited to, straight and branched chains such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

The term “alkoxy,” as used herein, refers to the group —OR*, wherein R*is a lower alkyl group.

The terms “halogen” or “halo,” as used herein, refer to chlorine,bromine, fluorine or iodine.

The terms “effective amount” and “therapeutically effective amount,” asused herein, refer to the amount of a compound of formula I that, whenadministered to a patient, is effective to at least partially treat acondition from which the patient is suffering from. Such conditionsinclude, but are not limited to, schizophrenia, schizoaffectivedisorder, schizophreniform disorder, L-DOPA-induced psychosis, bipolardisorder, obesity, obsessive compulsive disorder, depression, panicdisorder, sleep disorders, eating disorders, and epilepsy.

The term “pharmaceutically acceptable salts” or “pharmaceuticallyacceptable salt” includes acid addition salts, namely salts derived fromtreating a compound of formula I with an organic or inorganic acid suchas, for example, acetic, lactic, citric, cinnamic, tartaric, succinic,fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, or similarly known acceptable acids. In certain embodiments,the present invention provides the hydrochloride salt of a compound offormula I. Where the compound having formula I has an acidic function,for instance, where R², R³ or R⁴ is phenolic hydroxyl, the term“pharmaceutically acceptable salts” or “pharmaceutically acceptablesalt” includes salts derived from bases, for instance sodium salts.

The term “patient,” as used herein, refers to a mammal. In certainembodiments, the term “patient”, as used herein, refers to a human.

The terms “administer,” “administering,” or “administration,” as usedherein, refer to either directly administering a compound or compositionto a patient, or administering a prodrug derivative or analog of thecompound to the patient, which will form an equivalent amount of theactive compound or substance within the patient's body.

The terms “treat” or “treating,” as used herein, refers to partially orcompletely alleviating, inhibiting, preventing, ameliorating and/orrelieving the condition.

The terms “suffer” or “suffering” as used herein refers to one or moreconditions that a patient has been diagnosed with, or is suspected tohave.

2. Description of Exemplary Compounds

In certain embodiments, the invention relates to a compound of formulaI:

or pharmaceutically acceptable salts thereof, wherein:

-   each of R¹ and R^(1′) is independently hydrogen, methyl, ethyl,    2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl;-   each of R², R³ and R⁴ is independently hydrogen, halogen, OH, lower    alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN;-   Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally    substituted with one or more Rx groups;    each R^(x) is independently halogen, —OH, —CN, lower alkyl, lower    alkoxy, —CF₃, or —OCF₃; and    n is one or two.

In certain embodiments, the n group of formula I is 1.

In other embodiments, the n group of formula I is 2.

As defined generally above, each of the R¹ and R^(1′) groups of formulaI is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl. In certain embodiments, one of the R¹and R^(1′) groups of formula I is hydrogen and the other of R¹ andR^(1′) groups of formula I is hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl. In other embodiments, neither of theR¹ and R^(1′) groups of formula I is hydrogen. In still otherembodiments, both of the R¹ and R^(1′) groups of formula I are hydrogen.

As defined generally above, each of the R², R³ and R⁴ groups of formulaI is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy,trifluoromethyl, trifluoromethoxy, or CN. In certain embodiments, theR², R³ and R⁴ groups of formula I are all hydrogen. In otherembodiments, at least one of the R², R³ and R⁴ groups of formula I ishalogen. According to another aspect of the present invention, the R²group of formula I is hydrogen and the R³ and R⁴ groups of formula I areindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN. Yet another aspect of the present inventionprovides a compound of formula I wherein R² and R⁴ are both hydrogen andR³ is lower alkyl or lower alkoxy. Yet another aspect of the presentinvention provides a compound of formula I wherein R² and R⁴ are bothhydrogen and R³ is halogen. In certain embodiments, the R² and R⁴ groupsof formula I are both hydrogen and R³ is fluoro or chloro. In otherembodiments, the R² and R³ groups of formula I are both hydrogen and R⁴is fluoro or chloro.

As defined generally above, the Ar group of formula I is thienyl, furyl,pyridyl, or phenyl, wherein Ar is optionally substituted with one ormore R^(x) substituents, wherein each R^(x) is independently selectedfrom halogen, —OH, —CN, lower alkyl, lower alkoxy, —CF₃, or —OCF₃. Incertain embodiments, the Ar group of formula I is unsubstituted phenyl.In other embodiments, the Ar group of formula I is phenyl with at leastone substituent in the ortho position. In other embodiments, the Argroup of formula I is phenyl with at least one substituent in the orthoposition selected from halogen, lower alkyl, lower alkoxy, ortrifluoromethyl. According to one aspect the present invention providesa compound of formula I wherein Ar is phenyl di-substituted in the orthoand meta positions with halogen, lower alkyl, or lower alkoxy. Yetanother aspect of the present invention provides a compound of formula Iwherein Ar is phenyl di-substituted in the ortho and para positions withhalogen, lower alkyl, or lower alkoxy. Yet another aspect of the presentinvention provides a compound of formula I wherein Ar is phenyldi-substituted in both ortho positions with halogen, lower alkyl, orlower alkoxy. Exemplary substituents on the phenyl moiety of the Argroup of formula I include OMe, fluoro, chloro, methyl, andtrifluoromethyl.

In certain embodiments, the Ar group of formula I is selected from thefollowing:

According to another embodiment, the present invention provides acompound of formula II:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

According to yet another embodiment, the present invention provides acompound of formula III:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

According to yet another embodiment, the present invention provides acompound of formula IV:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

According to yet another embodiment, the present invention provides acompound of formula V:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

According to yet another embodiment, the present invention provides acompound of formula VI:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

According to yet another embodiment, the present invention provides acompound of formula VII:

or pharmaceutically acceptable salts thereof, wherein each R^(x) isindependently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN, and each of R¹, R^(1′), R², R³ and R⁴ are asdefined generally above and in classes and subclasses described aboveand herein.

It is recognized that atropisomers of the present compounds may exit.The present invention thus encompasses atropisomeric forms of compoundsof formula I as defined above, and in classes and subclasses describedabove and herein.

Exemplary compounds of formula I are set forth in Table 1, below.

TABLE 1 Exemplary Compounds of Formula I: I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

3. General Methods of Providing the Present Compounds

The 7-[biaryl]-1-benzofuran-2-yl}methyl)amines of formula I may beprepared as illustrated by the following schemes. An appropriatelysubstituted 2-bromo-6-hydroxybenzaldehyde or bromosalicylaldehyde (2) isreacted with diethyl bromomalonate in the presence of a suitable basesuch as potassium tert-butoxide in a solvent such tetrahydrofuran andethanol (Scheme 1) to provide 2-carboalkoxybenzofuran (3). Additionally,the 2-carboalkoxybenzofuran (3) may be prepared via cyclization of theappropriately substituted bromosalicylaldehyde with ethyl bromacetate inthe presence of a base such as potassium carbonate in a solvent such asN,N-dimethylformamide. The 2-bromo-6-hydroxybenzaldehydes appropriatefor the synthesis of compounds of formula I are either known compoundsor can be readily prepared by one skilled in the art. The resulting2-carboalkoxybenzofuran (3) is then hydrolyzed with aqueous sodiumhydroxide or other suitable alkoxide to provide a carboxylic acid thatcan then be reduced to the alcohol (4) by treatment with an appropriatereducing agent such as borane in tetrahydrofuran in a solvent such astetrahydrofuran. Treatment of the alcohol (4) with phthalimide understandard Mitsunobu conditions, such as triphenylphoshine anddiisopropylazodicarboxylate in a solvent such as toluene, provides thephthalimide (5). Introduction of the biaryl functionality is achieved bya palladium-catalyzed cross-coupling reaction (i.e. Suzuki reaction)with the desired boronic acid. Treatment of (5) with a catalyst such asdichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of asuitable base such as potassium carbonate in a solvent such as dioxaneprovides the biaryl product (5a). Subsequent removal of the phthalimidesystem by treatment of (5a) with methylamine in a solvent such asethanol provides the compounds of formula I. Treatment of thephthalimide derivative 5a with methylamine in ethanol allows the milddeprotection of the terminal amino group to give the primary amine,namely a compound having formula I where each of R¹ and R^(1′) ishydrogen. The primary amine may be converted into a secondary ortertiary amine conforming with formula I in known manner, for instance,by alkylation or reductive alkylation.

Alternatively, the biaryl system may be introduced directly onto the2-carboalkoxybenzofuran (3) via a palladium-catalyzed cross-couplingreaction (i.e. Suzuki reaction). Treatment of the2-carboalkoxy-7-methoxybenzofuran (3a) with boron tribromide (Scheme 1a)in a solvent such as dichloromethane provides the phenol (3b). Reactionof the phenol (3b) with trifluoromethanesulfonic anhydride in thepresence of a base such as triethylamine in a solvent such asdichloromethane provides the triflate (3c). Introduction of the biarylfunctionality is achieved by a palladium-catalyzed cross-couplingreaction (i.e. Suzuki reaction) with the desired boronic acid.Therefore, treatment of either (3) or (3a) with a catalyst such asdichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of asuitable base such as potassium carbonate in a solvent such as dioxaneprovides the biaryl product (3d). The carboalkoxy functionality presentin (3d) can be reduced with a suitable reducing agent such as lithiumborohydride in a solvent such as tetrahydrofuran to provide the alcohol(4a) directly. Reaction of the alcohol (4a) with phthalimide understandard Mitsunobu conditions, such as triphenylphoshine anddiisopropylazodicarboxylate in a solvent such as toluene, provides thephthalimide (5a).

For certain compounds of formula I, it is useful to introduce the biarylsystem at the beginning of the synthesis via a palladium-catalyzedcross-coupling reaction (i.e. Suzuki reaction) of an appropriatelysubstituted 2-methoxybromobenzene (6) with the desired boronic acid(Scheme 2). Treatment of (6) with a catalyst such astetrakis(triphenylphosphine)palladium(0) in the presence of a suitablebase such as potassium carbonate in a solvent such as ethylene glycoldimethyl ether provides the biaryl methoxybenzene (6a). Removal of themethoxy group in (6a) is accomplished with hydrogen bromide (30 wt % inacetic acid) to provide phenol (6b). The phenol (6b) is alkylated withan appropriately substituted allyl bromide or alcohol in the presence ofa suitable base such as potassium carbonate in a solvent such asN,N-dimethylformamide to afford the allyl ether (7). The resulting allylether (7) is treated in refluxing mesitylene or other suitable highboiling solvent to afford the desired Claisen rearrangement product (8).The double bond present in (8) is isomerized by refluxing withbis(acetonitrile)dichloropalladium(II) in a solvent such asdichloromethane to provide the 2-propenyl phenol (9). Oxidation of thedouble bond present in (9) by treatment with osmium tetroxide and sodiumperiodate in a solvent system such as tetrahydrofuran and water providesthe 2-hydroxybenzaldehyde (2c).

Alternatively, treatment of the methoxybenzene (6a) with bromine inacetic acid in the presence of iron(0) provides the2-bromomethoxybenzene (6c). Reaction of (6c) with isopropylmagnesiumchloride and 1-formylpiperidine in a solvent such as tetrahydrofuranaffords the 2-methoxybenzaldehyde (2d). Removal of the methyl group isaccomplished by reaction of the 2-methoxybenzaldehyde (2d) with borontribromide in a solvent such as dichloromethane to give the2-hydroxybenzaldehyde (2c).

Alternatively, treatment of the biaryl phenol (6b) with1,1-dichlorodimethyl ether in the presence of titanium tetrachloride ina solvent such as dichloromethane provides the 2-hydroxybenzaldehyde(2c) directly.

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials by methods generally available to one ofordinary skill in the art. Additional embodiments are exemplified inmore detail herein.

4. Uses, Formulation and Administration

Compounds of the present invention have affinity for and agonist orpartial agonist activity at the 2C subtype of brain serotonin receptorsand are thus of interest for the treatment of a variety of disordersand/or the alleviation of one or more associated symptoms. Suchdisorders associated with modulations of the 2C subtype of brainserotonin receptors are described in detail below. The present inventioncontemplates that compounds of the present invention are associated witha rapid onset of action. In addition, compounds of the present inventionlack the side-effect of sexual dysfunction.

Compounds of the present invention are useful for treating one or morepsychotic disorders, as described herein, without causingdiabetogenesis. Diabetogenesis is a side-effect associated with atypicalantipsychotic agents. Without wishing to be bound by any particulartheory, it is believed that the diabetogenesis associated with atypicalantipsychotic agents results from the fact that those agents are5-HT_(2C) antagonists. As described herein, the present compounds are5-HT_(2C) agonists, or partial agonists, and therefore are notassociated with diabetogenesis.

Compounds of the present invention are useful for treating one or morepsychotic disorders such as schizophrenia including paranoid type,disorganized type, catatonic type, and undifferentiated type,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, and psychotic disordernot otherwise specified; L-DOPA-induced psychosis; psychosis associatedwith Alzheimer's dementia; psychosis associated with Parkinson'sdisease; and psychosis associated with Lewy body disease.

Compounds of the present invention are also useful for treating symptomsrelated to psychotic disorders of the schizophrenic types, including theso called “positive” and “negative” symptoms of schizophrenia. Thesesymptoms include for example hallucinations, delusions, paranoia,anxiety, agitation, excessive aggression, tension, thought disorder,blunted affect, and social or emotional withdrawal in psychoticpatients. Other symptoms often associated with psychotic disordersinclude cognition disorders or deficits such as poor attention andimpaired function, depression, suicide, metabolic syndrome, andsubstance abuse. Thus, another embodiment of the present inventionprovides a method for treating one or more symptoms associated with apsychotic disorder.

In other embodiments, the present compounds are useful for treatinganxiety disorders such as panic attack, agoraphobia, panic disorder,specific phobia, social phobia, social anxiety disorder, obsessivecompulsive disorder, posttraumatic stress disorder, acute stressdisorder, generalized anxiety disorder, separation anxiety disorder,substance-induced anxiety disorder, and anxiety disorder not otherwisespecified.

According to another embodiment, the present compounds are useful fortreating bipolar disorders. Such bipolar disorders include bipolar Idisorder, bipolar II disorder, and cyclothymic disorder; bipolar mania,dementia, and depression with psychotic features. The present compoundsare also useful for treating (including the preventing) of cycling thatmay occur between bipolar depression and bipolar mania.

A more complete description of the aforementioned mental disorders canbe found in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) edition, Washington, D.C., American Psychiatric Association(1994), incorporated herein by reference in its entirety.

In certain embodiments, compounds of the present invention areadministered in combination with one or more anti-psychotic agents. Suchanti-psychotic agents are well known in the art and include clozapine(e.g., Clozaril®), risperidone (e.g., Risperidal®), olanzapine (e.g.,Zyprexa®), quetiapine (e.g., Seroquel®), ziprasidone (e.g., Geodon®),aripiprazole, amisulpiride, chlorpromazine, fluphenazine, haloperidol(e.g., Haldol®), loxapine, mesoridazine, molindone, perphenazine,pimozide, seroquel, sulpiride, thioridazine, thiothixene,trifluoperazine, and bifeprunox to name a few.

The combination of a compound of the present invention with one or moreanti-psychotic agents is useful for treating schizophrenia includingparanoid type, disorganized type, catatonic type, and undifferentiatedtype, schizophreniform disorder, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, and psychotic disordernot otherwise specified; L-DOPA-induced psychosis; psychosis associatedwith Alzheimer's dementia; psychosis associated with Parkinson'sdisease; psychosis associated with Lewy body disease; bipolar disorderssuch as bipolar I disorder, bipolar II disorder, and cyclothymicdisorder; bipolar mania, dementia, and depression with psychoticfeatures. In some embodiments, these combinations are useful in thetreatment of bipolar disorder, including for example treating thecycling between bipolar depression and bipolar mania.

In other embodiments, administration of a compound of the presentinvention with an anti-psychotic agent provide anti-psychotic benefitswhile eliminating or minimizing certain side affects (e.g., akathisia,dystonia, Parkinsonism dyskinesia and late dyskinesia and the like)typically observed when the anti-psychotic agent(s) is/are taken alone.

In other embodiments, compounds of the present invention are useful fortreating one or more depressive disorders such as major depressivedisorder, seasonal affective disorder, dysthymic disorder,substance-induced mood disorder, depressive disorder not otherwisespecified, and treatment resistant depression.

Another aspect of the present invention provides a method for treatingone or more mood episodes such as major depressive episode, manicepisode, mixed episode, and hypomanic episode; and adjustment disorderssuch as adjustment disorders with anxiety and/or depressed mood.

Compounds of the present invention are also useful for treating symptomsrelated to depressive disorders including somatic symptoms such asneuropathic pain and sexual dysfunction. Other somatic symptoms includehopelessness, helplessness, anxiety and worries, memory complaints withor without objective signs of cognitive impairment, loss of feeling ofpleasure (anhedonia), slowed movement, irritability, and lack ofinterest in personal care, such as poor adherence to medical or dietaryregimens.

In certain embodiments, the present invention provides a method oftreating sexual dysfunction related to depression. In other embodiments,the present invention provides a method of treating sexual dysfunctionassociated with administering a serotonin reuptake inhibitor (SRI) fortreating a depressive or other disorder. Such methods of treating sexualdysfunction are described in detail below.

In certain embodiments, compounds of the present invention areadministered in combination with one or more antidepressive agents.Suitable antidepressant agents include, for example, serotonin reuptakeinhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs), combinedserotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidaseinhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor(CRF) antagonists, alpha.-adrenoreceptor antagonists or other compoundsincluding atypical antidepressants. Additional antidepressants foradministering in combination with compounds of the present inventioninclude triple uptake inhibitors such as DOV 216303 and DOV 21947 . . .; melatonin agonists such as agomelotine, super neurotransmitter uptakeblockers (SNUBs; e.g., NS-2389 from GlaxoSmithKline and Neurosearch;(R)-DDMA from Sepracor), and/or substance P/neurokinin receptorantagonists (e.g., aprepitant/MK-869 from Merck; NKP-608 from Novartis;CPI-122721 from Pfizer; R673 from Roche; TAK637 from Takeda; andGW-97599 from GlaxoSmithKline).

Another class of antidepressant agents for administering in combinationwith compounds of the present invention are noradrenergic and specificserotonergic antidepressants (NaSSAs). A suitable example of a NaSSA ismirtazepine.

Suitable NRIs for administering in combination with compounds of thepresent invention include tertiary amine tricyclics and secondary aminetricyclics. Suitable examples of tertiary amine tricyclics include:amitriptyline, clomipramine, doxepin, imipramine (See U.S. Pat. No.2,554,736, incorporated herein by reference in its entirety) andtrimipramine, and pharmaceutically acceptable salts thereof. Suitableexamples of secondary amine tricyclics include: amoxapine, desipramine,maprotiline, nortriptyline and protriptyline, and pharmaceuticallyacceptable salts thereof.

Another NRI for administering in combination with compounds of thepresent invention is reboxetine (Edronax™;2-[.alpha.-(2-ethoxy)phenoxy-benzyl]morpholine, usually administered asthe racemate; See U.S. Pat. No. 4,229,449, incorporated herein byreference in its entirety).

Suitable SSRIs for administering in combination with compounds of thepresent invention include: citalopram(1-[3-(dimethylamino)propyl]-(4-fluorophenyl)-1,3-dihydro-o-5-isobenzofurancarbonitrile;See U.S. Pat. No. 4,136,193; Christensen et al., Eur. J. Pharmacol.41:153, 1977; Dufour et al., Int. Clin. Psychopharmacol. 2:225, 1987;Timmerman et al., ibid., 239, each of which is incorporated herein byreference in its entirety); fluoxetine(N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, marketed inthe hydrochloride salt form and as the racemic mixture of its twoisoforms; see, for example, U.S. Pat. No. 4,314,081; Robertson et al.,J. Med. Chem. 31:1412, 1988, each of which is incorporated herein byreference); fluoxetine/olanzapine in combination; fluvoxamine(5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanoneO-(2-aminoethyl)oxime; See U.S. Pat. No. 4,085,225; Claassen et al.,Brit. J. Pharmacol. 60:505, 1977; De Wilde et al., J. Affective Disord.4:249, 1982; Benfield et al., Drugs 32:313, 1986, each of which isincorporated herein by reference in its entirety); paroxetine(trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine;See U.S. Pat. No. 3,912,743; U.S. Pat. No. 4,007,196; Lassen, Eur. J.Pharmacol. 47:351, 1978; Hassan et al., Brit. J. Clin. Pharmacol.19:705, 1985; Laursen et al., Acta Psychiat. Scand. 71:249, 1985;Battegay et al., Neuropsychobiology 13:31, 1985, each of which isincorporated herein by reference in its entirety); sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylaminehydrochloride; See U.S. Pat. No. 4,536,518, incorporated herein byreference in its entirety); escitalopram (see U.S. Pat. RE34,712); andpharmaceutically acceptable salts thereof.

Suitable MAOIs for administering in combination with compounds of thepresent invention include: isocarboxazid, phenelzine, selegiline andtranylcypromine, and pharmaceutically acceptable salts thereof.

Suitable reversible MAOIs for administering in combination withcompounds of the present invention include: moclobemide(4-chloro-N-[2-(4-morpholinyl)-ethyl]benzamide; See U.S. Pat. No.4,210,754, incorporated herein by reference in its entirety),selegiline, and pharmaceutically acceptable salts thereof.

Suitable SNRIs for administering in combination with compounds of thepresent invention include venlafaxine (see U.S. Pat. No. 4,535,186,incorporated herein by reference in its entirety; see also U.S. Pat.Nos. 5,916,923, 6,274,171, 6,403,120, 6,419,958, 6,444,708, each ofwhich is incorporated herein by reference in its entirety), andpharmaceutically acceptable salts and analogs, including theO-desmethylvenlafaxine succinate salt; milnacipran(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide; see U.S.Pat. No. 4,478,836; Moret et al., Neuropharmacology 24:1211-19, 1985,each of which is incorporated herein by reference in its entirety);nefazodone (available from Bristol Myers Squibb and Dr. Reddy LabsInc.); duloxetine; and pharmaceutically acceptable salts thereof.

Suitable CRF antagonists for administering in combination with compoundsof the present invention include those compounds described inInternational Patent Specification Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677.

Suitable atypical antidepressants for administering in combination withcompounds of the present invention include: bupropion (Wellbutrin™;(.+−.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone),lithium, nefazodone, trazodone and viloxazine, and pharmaceuticallyacceptable salts thereof. Another suitable atypical antidepressant issibutramine.

Particular antidepressants for administering in combination withcompounds of the present invention include, but are not limited to,adinazolam, alaproclate, alnespirone, amineptine, amitriptyline,amitriptyline/chlordiazepoxide combination, amoxapine, aprepitant,atipamezole, azamianserin, bazinaprine, befuraline, bifemelane,binodaline, bipenamol, brofaromine, buproprion, caroxazone, cericlamine,cianopramine, cimoxatone, citalopram, clemeprol, clomipramine,clovoxamine, dazepinil, deanol, demexiptiline, desipramine,O-desmethylvenlafaxine, dibenzepin, dothiepin, doxepin, droxidopa,duloxetine, elzasonan, enefexine, eptapirone, escitalopram, estazolam,etoperidone, femoxetine, fengabine, fezolamine, fluotracen, fluoxetine,fluvoxamine, gepirone, idazoxan, imipramine, indalpine, indeloxazine,iprindole, isocarboxazid, levoprotiline, litoxetine, lofepramine,maprotiline, medifoxamine, metapramine, metralindole, mianserin,milnacipran, minaprine, mirtazapine, moclobemide, montirelin,nebracetam, nefopam, nefozodine, nemititide, nialamide, nomifensine,norfluoxetine, nortriptyline, orotirelin, oxaflozane, paroxetine,pheneizine, pinazepam, pirlindone, pizotyline, protryptiline,reboxetine, ritanserin, robalzotan, rolipram, selegiline, sercloremine,sertraline, setiptiline, sibutramine, sulbutiamine, sulpiride,sunepitron, teniloxazine, thozalinone, thymoliberin, tianeptine,tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine,tranylcypromine, trazodone, trimiprimine, venlafaxine, veralipride,vilazodone, viloxazine, viqualine, zimelidine and zometrapine, andpharmaceutically acceptable salts thereof, and St. John's wort herb, orHypencuin perforatum, or extracts thereof.

Suitable classes of anti-anxiety agents for administering in combinationwith compounds of the present invention include 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, neurokinin recepter(NK) antagonists (e.g., saredutant and osanetant) and corticotropinreleasing factor (CRF) antagonists. Suitable 5-HT_(1A) receptor agonistsor antagonists that may be used in the present invention include, inparticular, the 5-HT_(1A) receptor partial agonists buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof. An example of a compound with 5-HT_(1A) receptorantagonist/partial agonist activity is pindolol. new 5HT_(1A) agonistsvariza, alnespirone, gepirone, sunepitron, MKC242, vilazodone,eptapirone, and ORG12962 from Organon; new 5HT_(1A) antagonists such asrobalzotan; new 5-HT_(1B) agonists such as elzasonan; new 5HT₂antagonists such as YM-992 (from Yamanouchi Pharmaceuticals) andnemifitide.

According to the present invention, the inventive combinations may beadministered in conjunction with one or more other agents that is usefulin treating depression or other mood disorders. Alternatively oradditionally, inventive combinations may be administered with one ormore other pharmaceutical agents active in treating any other symptom ormedical condition present in the mammal that is related or unrelated tothe depression or mood disorder being experienced by the mammal.Examples of such pharmaceutical agents include, for example,anti-angiogenic agents, anti-neoplastic agents, anti-diabetic agents,anti-infective agents, pain-relieving agents, anti-psychotic agents,gastrointestinal agents, etc., or combinations thereof. Otherpharmaceutical agents useful in the practice of the present inventioninclude, for example, adjunctive therapies typically used to enhance theeffects of an antidepressant. Such adjunctive agents may include, forinstance, mood stabilizers (e.g., lithium, valproic acid, carbamazepine,etc.); pindolol, stimulants (e.g., methylphenidate, dextroamphetamine,etc.); or thyroid augmenting agents (e.g., T₃); anti-psychotics,anti-anxiety agents (e.g., benzodiazepines), and/or agents that relievesexual dysfunction (e.g., buspirone, which also has anti-anxietyeffects; dopaminergic agents such as amantadine, pramipexole, bupropion,etc.).

As 5-HT_(2C) modulators, compounds of the present invention are usefulfor treating a variety of disorders. Such disorders include premenstrualsyndrome (PMS), premenstrual dysphoric disorder (PMDD), motion or motordisorders such as Parkinson's disease; chronic fatigue syndrome,anorexia nervosa, disorders of sleep (e.g., sleep apnea), and mutism.

Premenstrual dysphoric disorder, or PMDD, is a severe form of PMS. LikePMS, PMDD typically occurs the week before the onset of menstruation anddisappears a few days after. PMDD is characterized by severe monthlymood swings and physical symptoms that interfere with everyday life,especially a woman's relationships with her family and friends. PMDDsymptoms go far beyond what are considered manageable or normalpremenstrual symptoms.

PMDD is a combination of symptoms that may include irritability,depressed mood, anxiety, sleep disturbance, difficulty concentrating,angry outbursts, breast tenderness and bloating. The diagnostic criteriaemphasize symptoms of depressed mood, anxiety, mood swings orirritability. The condition affects up to one in 20 American women whohave regular menstrual periods. According to another embodiment, thepresent invention provides a method for treating one or more symptomsassociated with PMDD.

Selective serotonin reuptake inhibitors (SSRIs) are the currentpreferred method for treating symptoms associated with PMDD. Accordingto another aspect, the present invention provides a method for treatingPMDD, or one or more symptoms associated with PMDD, by administering acompound of formula I in combination with an SSRI. In certainembodiments, the SSRI is fluoxetine, venlafaxine, paroxetine,duloxetine, or sertraline.

According to another embodiment, compounds of the present invention areuseful for treating a variety of eating disorders. In certainembodiments, the eating disorder is hyperphagia, bulimia or anorexianervosa. In certain embodiments, compounds of the present invention areuseful for treating gastrointestinal disorders, such as malfunction ofgastrointestinal motility or intestinal propulsion. Compounds of thepresent invention are also useful in connection with weight loss orcontrol (e.g., reduction in calorie or food intake, and/or appetitesuppression). Such methods are particularly useful for treating obesitywith its consequent comorbidities including diabetes insipidus, Type IIdiabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke,osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers,some infertility, and early mortality.

In certain embodiments, compounds of the present invention areadministered in combination with one or more anti-obesity agents. Suchanti-obesity agents are known in the art and include apolipoprotein-Bsecretion/microsomal triglyceride transfer protein (apo-B/MTP)inhibitors, 11β-hydroxy steroid dehydrogenase-1 (11(β-HSD type 1)inhibitors, PYY₃₋₃₆ and analogs thereof, MCR-4 agonists,cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (suchas sibutramine), sympathomimetic agents, R3 adrenergic receptoragonists, dopamine agonists (such as bromocriptine),melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptorantagonists (e.g., rimonabant), melanin concentrating hormoneantagonists, leptins (the OB protein), leptin analogs, leptin receptoragonists, galanin antagonists, lipase inhibitors (such astetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), Neuropeptide-Y receptor antagonists, thyromimeticagents, dehydroepiandrosterone or an analog thereof, glucocorticoidreceptor agonists or antagonists, orexin receptor antagonists, urocortinbinding protein antagonists, glucagon-like peptide-1 receptor agonists,ciliary neurotrophic factors (such as Axokine^(TA)), humanagouti-related proteins (AGRP), ghrelin receptor antagonists, histamine3 receptor antagonists or inverse agonists, and neuromedin U receptoragonists.

In other embodiments, a compound of the present invention isadministered in combination with an anti-obesity agent selected fromorlistat, sibutramine, bromocriptine, ephedrine, leptin, rimonabant,pseudoephedrine, PYY3.36 or an analog thereof, and2-oxo-N-(5-phenylpyrazinyl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide. According to another aspect of theinvention, a compound of the present invention is administered incombination with an anti-obesity agent in conjunction with typicaltreatments for obesity such as exercise and a sensible diet.

According to another embodiment, a compound of the present invention isadministered in combination with one or more agents for treatingdiabetes and associated conditions. In certain embodiments, a compoundof the present invention is administered in combination with one or moresuch agents including insulin and insulin analogs (e.g., LysProInsulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH₂;sulfonylureas and analogs thereof: chlorpropamide, glibenclamide,tolbutamide, tolazamide, acetohexamide, Glypizide®, glimepiride,repaglinide, meglitinide; biguanides: metformin, phenformin, buformin;“2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole,idazoxan, efaroxan, fluparoxan; other insulin secretagogues:linogliride, A-4166; glitazones: ciglitazone, Actos® (pioglitazone),englitazone, troglitazone, darglitazone, Avandia® (BRL49653); fatty acidoxidation inhibitors: clomoxir, etomoxir; glucosidase inhibitors:acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose,MDL-73,945; 13-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL316,243; or phosphodiesterase inhibitors: L-386,398.

In other embodiments, a compound of the present invention isadministered in combination with one or more lipid-lowering agents:benfluorex: vanadate and vanadium complexes (e.g., Nagiivan®) andperoxovanadium complexes; amylin antagonists; glucagon antagonists;gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents:nicotinic acid, acipimox, WAG 994, pramlintide (Symlin″), AC 2993,nateglinide, aldose reductase inhibitors (e.g., zopolrestat), glycogenphosphorylase inhibitors, sorbitol dehydrogenase inhibitors,sodium-hydrogen exchanger type 1 (NNE-1) inhibitors and/or cholesterolbiosynthesis inhibitors or cholesterol absorption inhibitors, especiallya HMG-CoA reductase inhibitor, or a HMG-CoA synthase inhibitor, or aHMG-CoA reductase or synthase gene expression inhibitor, a CETPinhibitor, a bile acid sequesterant, a fibrate, an ACAT inhibitor, asqualene synthetase inhibitor, or an anti-oxidant. In other embodiments,a compound of the present invention is administered in combination withone or more naturally occurring compounds that acts to lower plasmacholesterol levels. Such naturally occurring compounds are commonlyreferred to as nutraceuticals and include, for example, garlic extract,Hoodia plant extracts, and niacin.

In certain embodiments, compounds of the present invention are usefulfor inducing, assisting or maintaining desirable bladder control in amammal. The methods are particularly useful for treating a mammal thatis experiencing or susceptible to bladder instability or urinaryincontinence. Inventive methods include prevention, treatment orinhibition of bladder-related urinary conditions and bladderinstability, including idiopathic bladder instability, nocturnalenuresis, nocturia, voiding dysfunction and urinary incontinence(including, for example, stress incontinence, urge incontinence, and/ormixed incontinence). Also treatable or preventable by administration ofa compound of this invention is bladder instability secondary toprostate hypertrophy, as is a method for enhancing urethral tone andreducing undesirable urine leakage even in an otherwise healthy person.For example, the inventive methods are applicable to alleviating urineleakage often occurring in women during the first year after childbirth.

In other embodiments, the present compounds are useful for treatingurine retention or detrusor sphinctor dyssynergia. Patients sufferingfrom urine retention include those suffering from spinal cord injuriesor male patients with benign prostatic hyperplasia.

According to the present invention, a compounds of the present inventionis also useful in promoting the temporary delay of urination wheneverdesirable. Such compounds may be utilized in accordance with the presentinvention to stabilize the bladder in any applicable context. Inventivemethods therefore may be utilized to allow a recipient to control theurgency and frequency of urination.

In some embodiments of the invention, compounds of the present inventionare administered to a mammal in need thereof for the treatment,prevention, inhibition and/or amelioration of urge urinary incontinence(also known as bladder instability, neurogenic bladder, voidingdysfunction, hyperactive bladder, detrusor overactivity, detrusorhyper-reflexia or uninhibited bladder) or mixed urinary incontinence.Inventive uses include, but are not limited to, those for bladderactivities and instabilities in which the urinary urgency is associatedwith prostatitis, prostatic hypertrophy, interstitial cystitis, urinarytract infections or vaginitis. The methods of this invention may also beused to assist in inhibition or correction of the conditions ofFrequency-Urgency Syndrome, and lazy bladder, also known as infrequentvoiding syndrome.

Compounds of the present invention may also be used to treat, prevent,inhibit, or limit the urinary incontinence, urinary instability orurinary urgency associated with or resulting from administrations ofother medications, including diuretics, vasopressin antagonists,anticholinergic agents, sedatives or hypnotic agents, narcotics,alpha-adrenergic agonists, alpha-adrenergic antagonists, or calciumchannel blockers.

Compounds of the present invention are useful for inducing or assistingin urinary bladder control or preventing or treating the maladiesdescribed herein in humans in need of such relief, including adult andpediatric uses. They may also be utilized for veterinary applications,particularly including canine and feline bladder control methods. Ifdesired, the methods herein may also be used with farm animals, such asovine, bovine, porcine and equine breeds.

According to the present invention, compounds of the present inventionmay be administered alone to modulate bladder activity, or alternativelymay be administered in combination with (whether simultaneously orsequentially) one or more other pharmaceutical agents useful in themodulation of bladder activity. Alternatively or additionally, thecompounds of the present invention may be administered in combinationwith one or more other pharmaceutical agents useful in the treatment orprevention of one or more other symptoms, disorders, or diseasessuffered by the individual in need of bladder activity modulation.

Other pharmaceutical agents useful in the modulation of bladderactivity, and particularly for treatment, prevention, inhibition, and/oramelioration of urinary incontinence, include, for example, desmopressinacetate (available as DDAVP® Nasal Spray and DDAVP® tablets from AventisPharmaceuticals), as well as a desmopressin acetate rhinal tube(available from Ferring Pharmaceuticals Inc.). Other products include,for example, tolterodine tartrate (available as Detrol™ tablets fromPharmacia & Upjohn), oxybutinin chloride (available in the form ofDitropan® tablets and syrup and Ditropan XL® extended release tabletsfrom ALZA Pharmaceuticals), propanthaline bromide (available in tabletform from Roxane Laboratories, Inc.), hyoscyamine and hyoscyaminesulfate (available, respectively, as Cystopaz® tablets and Cystopaz-M®timed release capsules from PolyMedica Pharmaceuticals (U.S.A.), Inc.),hyoscyamine hydrobromide, flavoxate HCl (available in Urispas® 100 mgtablets from ALZA Pharmaceuticals), imipramine HCl (available in 10 mg,25 mg and 50 mg tablets from Geneva Pharmaceuticals, Inc.),phenylpropanolamine, midodrine HCl (available in 2.5 mg and 5 mgProamatine® tablets from Shire US Inc.), phenoxybenzamine HCl (availableas Dibenzyline® capsules from WellSpring Pharmaceuticals Corporation),and prazosin HCl (available in Minipress® capsules from Pfizer Inc.).Each of these medicaments may be administered in the pharmaceuticallyeffective amounts and regimens known in the art, including those listedin the Physicians' Desk Reference, 55 Edition, 2001, published byMedical Economics Company, Inc. at Monvale, N.J. 07645-1742, therelevant portions of which are incorporated herein by reference.

Yet other pharmaceutical agents that can act to modulate bladderactivity include, for example, other regulators of the 5HT_(2C)receptor. For example, United States Patent Application 2004/0235856(previously incorporated herein by reference in its entirety) describesa variety of 5HT_(2C) receptor modulators that are useful in accordancewith the practice of the present invention. Additional 5HT_(2C) agonistsare exemplified in Bishop et al., Expert Opin. Ther. Patent13:1691-1705, 2003, the entire contents of which are incorporated hereinby reference.

Still other pharmaceutical agents that can act to modulate bladderactivity include, for example, modulators of one or more KCNQ potassiumchannels. In some embodiments of the present invention, compounds of thepresent invention are administered in conjunction with one or moreagonists of KCNQ 2/3 or KCNQ3/5. Such KCNQ modulators include, forexample, compounds described in U.S. Pat. No. 5,384,330 and thosedescribed in U.S. Pat. No. 5,565,483, as well as those described inUnited States Patent Application Number 2002/0183395; and United StatesPatent Application Number 2004/0029949. The entire contents of each ofthese patents and patent applications is incorporated herein byreference. In some embodiments of the present invention, compounds ofthe present invention are administered with retigabine.

In some embodiments of the present invention, compounds of the presentinvention are administered in conjunction with one or more compoundswhich act as vasopressin agonists including, but not limited to thosedescribed in U.S. Pat. No. 6,194,407 (Fulli et al.), U.S. Pat. No.6,090,803 (Fulli et al.), U.S. Pat. No. 6,096,736 (Ogawa et al.), andU.S. Pat. No. 6,096,735 (Ogawa et al.).

In general, it will often be desirable in accordance with the presentinvention to administer one or more compounds of the present inventionin conjunction with one or more alpha-adrenergic receptor agonistsand/or one or more other sympathomimetic drugs.

According to the present invention, compounds of formula I may be usedto treat, prevent, or alleviate dependence, withdrawal, or symptomsthereof for any of a variety of substances including, for example,recreational substances (e.g., alcohol, tobacco [for example,nicotine]), pharmacologic agents (e.g., pain relievers [for example,Vicodin®, Lortab®, Lorcet®, Percocet®, Percodan®, Tylox®, Hydrocodone,OxyContin®, methadone, Tramadol, etc], tranquilizers, stimulants, orsedatives), and illicit drugs (e.g., marijuana, heroine, cocaine,ecstasy, LSD, PCP, methamphetamine, etc.).

The term “substance abuse”, as used herein, may be defined withreference to criteria set form in the Diagnostic and Statistical Manualof Mental Disorders, 4^(th) Ed. (1994) (“DSM-IV”), which was prepared bythe Task Force on Nomenclature and Statistics of the AmericanPsychiatric Association. A feature of substance abuse is a maladaptivepattern of substance use manifested by recurrent and significant adverseconsequences related to the repeated use of substances. As recited inthe DSM-IV, substance abuse is defined as maladaptive pattern ofsubstance abuse leading to clinicalyl significant impairment ordistress, as manifested by one (or more) of the following, occurringwithin a 12-month period: (1) recurrent substance use resulting in afailure to fulfill major role obligations at work, school, or home; (2)recurrent substance use in situations in which it is physicallyhazardous; (3) recurrent substance-related legal problems; and (4)continued substance use despite having persistent or recurrent social orinterpersonal problems cause or exacerbated by the effects of thesubstance. In addition, the DMS-IV requires that the symptoms ofsubstance abuse do not meet the criteria for substance dependence.

The term “substance dependence”, as used herein, may be defined withreference to criteria set form in the Diagnostic and Statistical Manualof Mental Disorders, 4^(th) Ed. (1994) (“DSM-IV”), which was prepared bythe Task Force on Nomenclature and Statistics of the AmericanPsychiatric Association. The criteria for substance dependence set forthin DSM-IV is a pattern of substance use, leading to clinicallysignificant impairment or distress as manifested by at least threeselected from the following group, occurring at any time within the sametwelve month period: (1) tolerance as defined by either (a) a need forsubstantially increased amounts of the substance to achieve the desiredeffect; or (b) substantially diminished effect with continued use of thesame amount of the substance; (2) withdrawal, as demonstrated by either(a) the characteristic withdrawal syndrome for the specific substance;or (b) the same, or a closely related substance is taken to relieve oravoid withdrawal symptoms; (3) the substance is often taken in largeramounts or over a longer period then was intended; (4) there is apersistent desire or unsuccessful efforts to cut down or controlsubstance use; (5) a great deal of time is spent in activities to obtainthe substance, use the substance, or recover from its effects; (6)important social, occupational or recreational activities are given upor reduced because of substance use; and (7) the substance use iscontinued despite knowledge of having a persistent or recurrent physicalor psychological problem that is likely to have been caused orexacerbated by the substance. Substance dependence can be withphysiological dependence; that is evidence of tolerance or withdrawal ispresent, or without physiological dependence, where no evidence oftolerance or withdrawal is present. Four of the conditions set forth inDSM-IV include remission. These types of remission are based on theinterval of time that has elapsed since the cessation of dependenciesand whether there is continued presence of one or more of the symptomsincluded in the criteria for dependencies.

In certain embodiments, compounds of the present invention are usefulfor treating alcoholism (e.g., alcohol abuse, addiction and/ordependence including treatment for abstinence, craving reduction andrelapse prevention of alcohol intake) and/or tobacco abuse (e.g.,smoking addiction, cessation and/or dependence including treatment forcraving reduction and relapse prevention of tobacco smoking).

In evaluating substance abuse in accordance with the present invention,reference may be made, for example, to the National Survey on Drug Useand Health (NSDUH), which obtains information on nine differentcategories of illicit drug use: marijuana, cocaine, heroin,hallucinogens, inhalants, and nonmedical use of prescription-type painrelievers, tranquilizers, stimulants, and sedatives. In thesecategories, hashish is included with marijuana, and crack is considereda form of cocaine. Several drugs are grouped under the hallucinogenscategory, including LSD, PCP, peyote, mescaline, mushrooms, and“Ecstasy” (MDMA). Inhalants include a variety of substances, such asamyl nitrite, cleaning fluids, gasoline, paint, and glue. The fourcategories of prescription-type drugs (pain relievers, tranquilizers,stimulants, and sedatives) cover numerous drugs available throughprescriptions and sometimes illegally “on the street.” Methamphetamineis considered a type of stimulant. Respondents are asked to report onlyuses of drugs that were not prescribed for them or drugs they took onlyfor the experience or feeling they caused. Over-the-counter drugs andlegitimate uses of prescription drugs are not included. NSDUH reportscombine the four prescription-type drug groups into a category referredto as “any psychotherapeutics.”

The NSDUH categorizes alcohol abuse through use of questions about thefrequency of the consumption of alcoholic beverages, such as beer, wine,whiskey, brandy, and mixed drinks. An extensive list of examples of thekinds of beverages covered is given to respondents prior to the questionadministration. A “drink” is defined as a can or bottle of beer, a glassof wine or a wine cooler, a shot of liquor, or a mixed drink with liquorin it. Times when the respondent only had a sip or two from a drink arenot considered as consumption. For this report, estimates for theprevalence of alcohol use are reported primarily at three levels definedfor both males and females and for all ages as follows:

Current use—At least one drink in the past 30 days (includes binge andheavy use).Binge use—Five or more drinks on the same occasion at least once in thepast 30 days (includes heavy use).Heavy use—Five or more drinks on the same occasion on at least 5different days in the past 30 days

The NSDUH also characterizes the use of tobacco products, includingcigarettes, chewing tobacco, snuff, cigars, and pipe tobacco. Foranalytic purposes, data for chewing tobacco and snuff are combined as“smokeless tobacco.” Cigarette use is defined as smoking “part or all ofa cigarette.” Questions to determine nicotine dependence among currentcigarette smokers also are included in NSDUH. Nicotine dependence isbased on criteria from the Nicotine Dependence Syndrome Scale (NDSS) orthe Fagerstrom Test of Nicotine Dependence (FTND).

In other embodiments, compounds of the present invention are useful fortreating withdrawal from drug addiction including addiction to nicotine,alcohol, and other substances of abuse. Individuals often suffer thesymptoms of nicotine withdrawal as a consequence of the discontinued useof tobacco in any form, including, but not limited to smoking ofcigarette, cigar, or pipe tobacco, or the oral or intranasal ingestionof tobacco or chewing tobacco. Such oral or intranasal tobacco includes,but is not limited to snuff and chewing tobacco. The cessation ofnicotine use or reduction in the amount of nicotine use, is oftenfollowed within 24 hours by symptoms including dysphoric, depressedmood; light-headedness; insomnia; irritability, frustration or anger;anxiety; nervous tremor; difficulty concentrating; restlessness;decreased heart rate; increased appetite or weight gain; and the cravingfor tobacco or nicotine. These symptoms often cause clinicallysignificant distress or impairment in social, occupational, or otherimportant areas of functioning.

The discontinued or reduction in administration of an opioid, typicallyself-administration, through injection or orally, through smoking orintranasal ingestion, often results in the presence of a characteristicopioid withdrawal condition. This withdrawal condition can also beprecipitated by administration of an opioid antagonist such as naloxoneor naltrexone after opioid use. Opioid withdrawal is characterized bysymptoms that are generally opposite to the opioid agonist effects.These withdrawal symptoms may include anxiety; restlessness; muscleaches, often in the back and legs; craving for opioids; irritability andincreased sensitivity to pain; dysphoric mood; nausea or vomiting;lacrimation; rhinorrhoea; papillary dilation; piloerection; sweating;diarrhea; yawning; fever; and insomnia. When dependence is onshort-acting opioids, such as heroin, withdrawal symptoms usually occurwithin 6-24 hours after the last dose, while with longer-acting opioids,such as methadone, symptoms may take 2-4 days to emerge. These symptomsoften cause clinically significant distress or impairment in social,occupational or other important areas of functioning. The presentinvention is most preferably used to alleviate one or more symptomsattributed to opioid withdrawal when such symptoms are not due to ageneral medical condition and are not better accounted for by anothermedical disorder.

The discontinued or reduction in use of ethanol (ethanol containingbeverages) results in the onset of ethanol withdrawal conditions.Ethanol withdrawal conditions are characterized by symptoms that beginwhen blood concentrations of ethanol decline sharply, within 4 to 12hours after ethanol use has been stopped or reduced. These ethanolwithdrawal symptoms include craving for ethanol; autonomic hyperactivity(such as sweating or pulse rate greater than 100); hand tremor;insomnia; nausea; vomiting; transient visual, tactile, or auditoryhallucinations or illusions; psychomotor agitation; anxiety; and grandmal seizures. These symptoms often cause clinically significant distressor impairment in social, occupational, or other important areas offunctioning. The present invention is most preferably used to alleviateone or more symptoms attributed to ethanol withdrawal when such symptomsare not due to a general medical condition and are not better accountedfor by another medical disorder.

According to another embodiment, a compound of the present invention isadministered in combination with one or more agents useful for treatingsubstance abuse. In certain embodiments, a compound of the presentinvention is administered in combination with one or more agents totreat tobacco abuse. Such agents include nicotine receptor partialagonists bupropion hypochloride (Zyban™) and nicotine replacementtherapies.

According to yet another embodiment, a compound of the present inventionis administered in combination with one or more agents to treatalcoholism, such as opioid antagonists (e.g., naltrexone, ReVia™),nalmefene, disulfuram (Antabuse™), and acamprosate (Campral™).

In certain embodiments, a compound is administered in combination withone or more agents for reducing alcohol withdrawal symptoms such asbenzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin™). In other embodiments of the invention,therapy utilizing compounds of the present invention is administeredconcomitantly with, in connection with, and/or subsequent to aneducational and/or behavioral modification program to enhance continuedabstinence from substance dependence or abuse. The method of the presentinvention may be particularly useful in treating symptoms of withdrawaloften observed in rehabilitation or other treatment programs. Therefore,the programs can be more effective by focusing on educational andbehavioral modification goals, further reducing the incidence of programnon-completion.

In certain embodiments, compounds of the present invention are usefulfor treating one or more intellectual deficit disorders comprisingadministering a compound of the present invention. In other embodiments,such intellectual deficit disorders include dementia, such as dementiaof aging, vascular dementia, mild cognitive impairment, age-relatedcognitive decline, and mild neurocognitive disorder; Alzheimer'sdisease, and memory deficit, attention deficit disorders (ADD, alsoknown as Attention Deficit Hyperactivity Disorder or ADHD) in bothchildren and adults. In certain embodiments, the present inventionprovides a method of treating ADD and/or ADHD in a pediatric patientcomprising administering to said patient a compound of formula I orpharmaceutical composition thereof.

In other embodiments, the present invention provides a method oftreating one or more cognition disorders. According to another aspect,the cognition disorder is a learning disorder. Such learning disordersare known in the art and include autism, dyslexia, Asperger's syndrome,a neurobiological disorder similar to autism and characterized byserious deficits in social and communication skills; specific learningdisability, a disorder in one or more of the basic psychologicalprocesses involved in understanding or in using spoken or writtenlanguage, which may manifest itself in an imperfect ability to listen,think, speak, read, write, spell or to do mathematical calculations;dysgraphia, a disorder that causes difficulty with forming letters orwriting within a defined space; dyscalculia, a disorder that causespeople to have problems doing arithmetic and grasping mathematicalconcepts; dyspraxia, a problem with the body's system of motion thatinterferes with a person's ability to make a controlled or coordinatedphysical response in a given situation; visual perceptual deficit,difficulty receiving and/or processing accurate information from thesense of sight, although there is nothing wrong with vision; andauditory perceptual deficit, difficulty receiving accurate informationthrough auditory means, even though there is no problem with hearing.

In certain embodiments, the present invention provides a method fortreating one or more impulsivity disorders (e.g. borderline personalitydisorder), disruptive behavior disorders, or impulse control disorders.In certain embodiments, the present invention provides a method fortreating Tourette's syndrome (TS), an inherited, neurological disordercharacterized by repeated and involuntary body movements (tics) and/oruncontrollable vocal sounds.

According to another aspect, the present invention provides a method fortreating one or more behavioral addictions and addictive disorders.Behavioral addictions and addictive disorders result from theintoxication one senses from the release of brain chemicals (e.g.,serotonin, adrenaline, epinepherine, etc.) during certain activities.Such disorders are known in the art and include gambling, sex addiction,eating disorders, spending addiction, rage/anger, workaholism, exerciseaddiction, risk taking addictions, and perfectionism to name a few.

In certain embodiments, a compound of the present invention isadministered in combination with one or more cognitive improvementagents. Such agents are well known in the art and include donepezilhydrochloride (Aircept™) and other acetylcholinesterase inhibitors;galantamine, neuroprotective agents (e.g., memantine); ADD/ADHD agents(e.g., methylphenidate (Ritalin™), atomoxetine (Strattera™),methylphenidate, sustained release (Concerta™) andamphetamine/dextroamphetamine (Adderall™).

According to another aspect, the present invention provides a method fortreating sexual dysfunction comprising administering a compound of thepresent invention. In certain embodiments, the sexual dysfunction isassociated with a depressive disorder. In other embodiments, the sexualdysfunction is associated with treatment of a disorder by administrationof a serotonin reuptake inhibitor. Compounds of the present inventionare useful for treating sexual dysfunction in the male and in thefemale. Such disorders include male erectile dysfunction (MED) andfemale sexual dysfunction (FSD), e.g. female sexual arousal disorder(FSAD).

In other embodiments, the present invention provides a method fortreating one or more disorders associated with sexual dysfunctionincluding: HSDD, characterized by a deficiency, or absence of, sexualfantasies and desire for sexual activity; FSAD, characterized by apersistent or recurrent inability to attain, or to maintain untilcompletion of the sexual activity, an adequate lubrication-swellingresponse of sexual excitement; FOD characterized by persistent orrecurrent delay in, or absence of, orgasm following a normal sexualexcitement phase; Sexual Pain Disorders such as dyspareunia andvaginismus; and/or HSDD characterized by a woman who has no or littledesire to be sexual, and has no or few sexual thoughts or fantasies.

According to another embodiment, a compound of the present invention isadministered in combination with one or more agents for treating malesexual dysfunction (e.g., male erectile dysfunction). Such agents areknown in the art and include a dopaminergic agent (e.g. D2, D3 or D4agonists and apomorphine); an NPY (neuropeptide Y) (preferably an NPY-1and/or NPY-5 inhibitor); a melanocortin receptor agonist or modulator ormelanocortin enhancer; an NEP inhibitor; a PDE inhibitor (preferably, acGMP PDE-5 inhibitor); a bombesin receptor antagonist or modulator, anda soluble secreted endopeptidase inhibitor (SEPi). In certainembodiments, a compound of the present invention is administered incombination with one or more agents for treating male sexual dysfunctionsuch as alprostadil or sildenafil.

According to yet another embodiment, a compound of the present inventionis administered in combination with one or more agents for treatingfemale sexual dysfunction. Such agents are known in the art and includeestrogen receptor modulators (e.g., estrogen agonists and/or estrogenantagonists); testosterone replacement agents, testosternone(Tostrelle), dihydrotestosterone, dehydroepiandrosterone (DHEA), atestosterone implant; eg dehydroandrostendione, estrogen, estrogen,medroxyprogesterone, medroxyprogesterone acetate (MPA), a combination ofestrogen and a methyl testosterone hormone replacement therapy agent;Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, EllesteSolo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase,Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone, adopaminergic agent; eg apomorphine or a selective D2, D3 or D2/D₃agonistsuch as, pramipexole and ropirinol, a NPY (neuropeptide Y) inhibito; ega NPY (neuropeptide Y) inhibitor such as a NPY1 or NPY5 inhibitor,preferably NPY1 inhibitor, a melanocortin receptor modulator or amelanocortin enhancer; eg melanotan II, PT-14, PT-141, a NEP (neutralendopeptidase) inhibitor; a PDE (phosphodiesterase) inhibitor; egsildenafil, and/or a bombesin receptor modulator.

According to the present invention, compounds of the present inventionare useful for treating any of a variety of different types of painexperienced by mammals, such as humans. For example, the compounds ofthe present invention may be used to treat treating acute pain (shortduration) or chronic pain (regularly reoccurring or persistent), whethercentralized or peripheral.

Examples of pain that can be acute or chronic and that can be treated inaccordance with the methods of the present invention includeinflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain,neck or upper back pain, visceral pain, somatic pain, neuropathic pain,cancer pain, pain caused by injury or surgery such as burn pain, orheadaches such as migraines or tension headaches, or combinations ofthese pains. One skilled in the art will recognize that these pains mayoverlap one another. For example, a pain caused by inflammation may alsobe visceral or musculoskeletal in nature.

In one embodiment of the present invention, one or more compounds of thepresent invention is/are administered in mammals to treat chronic painsuch as neuropathic pain associated for example with damage to orpathological changes in the peripheral or central nervous systems;cancer pain; visceral pain associated with for example the abdominal,pelvic, and/or perineal regions or pancreatitis; musculoskeletal painassociated with for example the lower or upper back, spine,fibromylagia, temporomandibular joint, or myofascial pain syndrome; bonypain associated with for example bone or joint degenerating disorderssuch as osteoarthritis, rheumatoid arthritis, or spinal stenosis;headaches such migraine or tension headaches; or pain associated withinfections such as HIV, sickle cell anemia, autoimmune disorders,multiple sclerosis, or inflammation such as osteoarthritis or rheumatoidarthritis.

In some embodiments, the compounds of the present invention are used totreat chronic pain that is neuropathic pain, visceral pain,musculoskeletal pain, bony pain, headache, cancer pain or inflammatorypain or combinations thereof, in accordance with the methods describedherein. Inflammatory pain can be associated with a variety of medicalconditions such as osteoarthritis, rheumatoid arthritis, surgery, orinjury. Neuropathic pain may be associated with for example diabeticneuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminalneuralgia, lumbar or cervical radiculopathies, fibromyalgia,glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia,thalamic syndrome, nerve root avulsion, or nerve damage cause by injuryresulting in peripheral and/or central sensitization such as phantomlimb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer,chemical injury, toxins, nutritional deficiencies, or viral or bacterialinfections such as shingles or HIV, or combinations thereof. Inventivetreatment methods further include treatments in which the neuropathicpain is a condition secondary to metastatic infiltration, adiposisdolorosa, burns or central pain conditions related to thalamicconditions.

Neuropathic pains described above may also be, in some circumstances,classified as “painful small fiber neuropathies” such as idiopathicsmall-fiber painful sensory neuropathy, or “painful large fiberneuropathies” such as demylinating neuropathy or axonal neuropathy, orcombinations thereof. Such neuropathies are described in more detail,for example, in the J. Mendell et al., N. Engl. J. Med. 2003,348:1243-1255, which is hereby incorporated by reference in itsentirety.

In another embodiment, the compounds useful in the present invention maybe administered to totally or partially inhibit a neuropathic paincondition from developing. For example, compounds of the presentinvention may be administered to a mammal who is at risk for developinga neuropathic pain condition such as a mammal who has contractedshingles or a mammal who is being treated for cancer.

In one embodiment, the compounds useful in the present invention may beadministered prior to or during a surgical procedure to partially ortotally inhibit development of pain associated with the surgicalprocedure.

As mentioned previously, the methods of the present invention may beused to treat pain that is somatic and/or visceral in nature. Forexample, somatic pain that can be treated in accordance with the methodsof the present invention includes pain associated with structural orsoft tissue injury experienced during surgery, dental procedures, burns,or traumatic body injuries. Examples of visceral pain that can betreated in accordance with the methods of the present invention includethose types of pain associated with or resulting from maladies of theinternal organs such as ulcerative colitis, irritable bowel syndrome,irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors,gastritis, pancreatitis, infections of the organs, or biliary tractdisorders, or combinations thereof. One skilled in the art will alsorecognize that the pain treated according to the methods of the presentinvention may also be related to conditions of hyperalgesia, allodynia,or both. Additionally, chronic pain to be treated in accordance with thepresent invention may be with or without peripheral or centralsensitization.

The present invention also provides use of the compounds of the presentinvention to treat acute and/or chronic pains associated with femaleconditions, which may also be referred to as female-specific pain. Suchtypes of pain include those that are encountered solely or predominatelyby females, including pain associated with menstruation, ovulation,pregnancy or childbirth, miscarriage, ectopic pregnancy, retrogrademenstruation, rupture of a follicular or corpus luteum cyst, irritationof the pelvic viscera, uterine fibroids, adenomyosis, endometriosis,infection and inflammation, pelvic organ ischemia, obstruction,intra-abdominal adhesions, anatomic distortion of the pelvic viscera,ovarian abscess, loss of pelvic support, tumors, pelvic congestion orreferred pain from non-gynecological causes.

In certain embodiments, a compound of the present invention isadministered in combination with a pain relieving agent. Examples ofpain relieving agents that may be administered with compounds of thepresent invention include, but are not limited to, analgesics such asnon-narcotic analgesics or narcotic analgesics; anti-inflammatory agentssuch as non-steroidal anti-inflammatory agents (NSAIDs), steroids oranti-rheumatic agents; migraine preparations such as beta adrenergicblocking agents, ergot derivatives, or isometheptene; tricyclicantidepressants such as amitryptyline, desipramine, or imipramine;anti-epileptics such as gabapentin, carbamazepine, topiramate, sodiumvalproate or phenyloin; α₂ agonists; or selective serotonin reuptakeinhibitors/selective norepinepherine uptake inhibitors, or combinationsthereof.

One skilled in the art will recognize that some agents described hereinact to relieve multiple conditions such as pain and inflammation, whileother agents may just relieve one symptom such as pain. A specificexample of an agent having multiple properties is aspirin, where aspirinis anti-inflammatory when given in high doses, but at lower doses isjust an analgesic. The pain relieving agent may include any combinationof the aforementioned agents, for example, the pain relieving agent maybe a non-narcotic analgesic in combination with a narcotic analgesic.

Non-narcotic analgesics useful in the practice of the present inventioninclude, for example, salicylates such as aspirin, ibuprofen (Motrin®,Advil®), ketoprofen (Orudis®), naproxen (Naprosyn®), acetaminophen,indomethacin or combinations thereof. Examples of narcotic analgesicagents that may be used in combination with compounds of the presentinvention include opioid analgesics such as fentenyl, sufentanil,morphine, hydromorphone, codeine, oxycodone, buprenorphine orpharmaceutically acceptable salts thereof or combinations thereof.Examples of anti-inflammatory agents that may be used in combinationwith compounds of the present invention include but are not limited toaspirin; ibuprofen; ketoprofen; naproxen; etodolac (Lodine®); COX-2inhibitors such as celecoxib (Celebrex™), rofecoxib (Vioxx®), valdecoxib(Bextra®), parecoxib, etoricoxib (MK663), deracoxib,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide,darbufelone, flosulide,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),meloxicam, nimesulide,1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo-butenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, or their physiologically acceptable salts, esters orsolvates; sulindac (Clinoril®); diclofenac (Voltaren®); piroxicam(Feldene®); diflunisal (Dolobid®), nabumetone (Relefen®), oxaprozin(Daypro®), indomethacin (Indocin®); or steroids such as Pediaped®prednisolone sodium phosphate oral solution, Solu-Medrol®methylprednisolone sodium succinate for injection, Prelone® brandprednisolone syrup.

Further examples of anti-inflammatory agents that may be used fortreating pain, for example associated with rheumatoid arthritis, inaccordance with the present invention include naproxen, which iscommercially available in the form of EC-Naprosyn® delayed releasetablets, Naprosyn®, Anaprox® and Anaprox® DS tablets and Naprosyn®suspension from Roche Labs, Celebrex® brand of celecoxib tablets, Vioxx®brand of rofecoxib, Celestone® brand of betamethasone, Cupramine® brandpenicillamine capsules, Depen® brand titratable penicillamine tablets,Depo-Medrol® brand of methylprednisolone acetate injectable suspension,Arava™ leflunomide tablets, Azulfidine EN-tabs® brand of sulfasalazinedelayed release tablets, Feldene® brand piroxicam capsules, Cataflam®diclofenac potassium tablets, Voltaren® diclofenac sodium delayedrelease tablets, Voltaren®-XR diclofenac sodium extended releasetablets, or Enbrel® etanerecept products.

Examples of yet other agents used to treat inflammations, especiallyrheumatoid arthritis, include immunosuppressants such as Gengraf™ brandcyclosporine capsules, Neoral® brand cyclosporine capsules or oralsolution, or Imuran® brand azathioprine tablets or IV injection;Indocin® brand indomethacin capsules, oral suspension or suppositories;Plaquenil® brand hydroxychloroquine sulfate; or Remicade® infliximabrecombinant for IV injection; or gold compounds such as auranofin orMyochrisyine® gold sodium thiomalate injection.

As 5-HT_(2C) modulators, compounds of the present invention are usefulfor treating a variety of disorders. Such disorders include premenstrualsyndrome, motion or motor disorders such as Parkinson's disease andepilepsy; migraines, chronic fatigue syndrome, anorexia nervosa,disorders of sleep (e.g., sleep apnea), and mutism.

In other embodiments, compounds of the present invention are useful fortreating one or more central nervous system deficiencies associated, forexample, with trauma, stroke, and spinal cord injuries,neurodegenerative diseases or toxic or infective CNS diseases (e.g.,encephalitis or meningitis), or Parkinson's disease. The compounds ofthe present invention can therefore be used to improve or inhibitfurther degradation of central nervous system activity during orfollowing the malady or trauma in question. Included in theseimprovements are maintenance or improvement in motor and motilityskills, control, coordination and strength.

5. Pharmaceutically Acceptable Compositions

In other embodiments, the invention relates to compositions comprisingat least one compound of formula I or VII, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, excipients, or diluents. Such compositions includepharmaceutical compositions for treating or controlling disease statesor conditions of the central nervous system. In certain embodiments, thecompositions comprise mixtures of one or more compounds of formula I orVII.

In certain embodiments, the invention relates to compositions comprisingat least one compound of formula I or VII, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, excipients, or diluents. Such compositions are prepared inaccordance with acceptable pharmaceutical procedures, such as, forexample, those described in Remingtons Pharmaceutical Sciences, 17thedition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa.(1985), which is incorporated herein by reference in its entirety.Pharmaceutically acceptable carriers are those carriers that arecompatible with the other ingredients in the formulation and arebiologically acceptable.

The compounds of formula I or VII can be administered orally orparenterally, neat, or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substancesthat can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders,tablet-disintegrating agents, or encapsulating materials. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water,an organic solvent, a mixture of both, or a pharmaceutically acceptableoil or fat. The liquid carrier can contain other suitable pharmaceuticaladditives such as, for example, solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers orosmo-regulators. Suitable examples of liquid carriers for oral andparenteral administration include water (particularly containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be administered by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

The compounds of formula I or VII can be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of formula I or VII can be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of formula I can also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon-toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier can take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient can also besuitable. A variety of occlusive devices can be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form.

The amount of compound of formula I or VII provided to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compounds of formula I are provided to a patient sufferingfrom a condition in an amount sufficient to treat or at least partiallytreat the symptoms of the condition and its complications. An amountadequate to accomplish this is a “therapeutically effective amount” asdescribed previously herein. The dosage to be used in the treatment of aspecific case must be subjectively determined by the attendingphysician. The variables involved include the specific condition and thesize, age, and response pattern of the patient. The treatment ofsubstance abuse follows the same method of subjective drugadministration under the guidance of the attending physician. Generally,a starting dose is about 5 mg per day with gradual increase in the dailydose to about 150 mg per day, to provide the desired dosage level in thepatient.

In certain embodiments, the present invention is directed to prodrugs ofcompounds of formula I. The term “prodrug,” as used herein, means acompound that is convertible in vivo by metabolic means (e.g. byhydrolysis) to a compound of formula I. Various forms of prodrugs areknown in the art such as those discussed in, for example, Bundgaard,(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen,et al., (ed). “Design and Application of Prodrugs, Textbook of DrugDesign and Development, Chapter 5, 113-191 (1991), Bundgaard, et al.,Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard, J. ofPharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella(eds.) Prodrugs as Novel Drug Delivery Systems, American ChemicalSociety (1975), each of which is hereby incorporated by reference in itsentirety.

EXAMPLES

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, in addition to the Schemes set forth above and othermethods known to one of ordinary skill in the art, can be applied to allcompounds and subclasses and species of each of these compounds, asdescribed herein.

Intermediate 1

(7-bromo-5-chloro-1-benzofuran-2-yl)methanol: To a solution of3-bromo-5-chloro-2-hydroxybenzaldehyde (47.09 g, 0.20 mol) in (1:1)tetrahydrofuran:ethanol (1000 mL) was added diethyl bromomalonate (57.38g, 0.24 mol) and potassium tert-butoxide (26.93 g, 0.24 mol) and thereaction mixture was heated at 70° C. for 12 h. The reaction mixture wasallowed to cool to room temperature and the solvent was removed in vacuoto provide a crude solid. The solid was dissolved in tetrahydrofuran(1000 mL) and aqueous sodium hydroxide (1.0 M, 250 mL) was added and thereaction mixture was allowed to stir at room temperature for 4 h. Thereaction mixture was acidified (pH 1-2) with concentrated aqueoushydrogen chloride and the aqueous layer was extracted with ethyl acetate(3×250 mL), the combined organic layers washed with water (2×250 mL),saturated aqueous sodium chloride (250 mL), dried (magnesium sulfate),and the solvent removed in vacuo to provide the carboxylic acid as acrude solid. To a solution of the carboxylic acid (2.75 g, 0.01 mol) intetrahydrofuran (100 mL) cooled to 0° C. was addedborane-tetrahydrofuran complex (1.0 M, 30 mL) and the reaction mixturewas allowed to stir at room temperature for 12 h. The reaction mixturewas quenched by the slow addition of methanol. The solvent was removedin vacuo and the residue was purified by flash column chromatography(silica, ethyl acetate:hexanes 3:7) to provide(7-bromo-5-chloro-1-benzofuran-2-yl)methanol 1.59 g (61%) as a whitesolid. mp 123-126° C.; Anal. calcd for C₉H₉BrClO₂: C, 41.34; H, 2.31.Found: C, 41.68; H, 2.04.

Intermediate 2

2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione:To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50mL) cooled to 0° C. was added the diisopropylazadicarboxylate (1.11 g,5.48 mmol) followed by the phthalimide (0.81 g, 5.48 mmol) and thereaction mixture allowed to stir for 10 min. The(7-bromo-5-chloro-1-benzofuran-2-yl)methanol (1.37 g, 5.22 mmol) wasthen added and the reaction was allowed to stir at 0° C. an additional 1h. The reaction mixture was then quenched with water (1 mL) and thesolvent was removed in vacuo to provide a crude solid. The solid wassuspended in water (100 mL) and the aqueous layer was extracted withethyl acetate (3×100 mL), the combined organic extracts were washed withsaturated aqueous sodium chloride (50 mL), dried (magnesium sulfate),and the solvent removed in vacuo to provide a crude residue.Purification by flash column chromatography (silica, ethylacetate:hexanes 1:5) provided 1.73 g (85%) of2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dioneas a white solid. mp 194-198° C.; HRMS-ESI (m/z): [M+H]⁺ calcd forC₁₇H₉BrClNO₃, 388.94545; found, 389.9553.

Intermediate 3

2-[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione:To a suspension of the2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione(0.500 g, 1.28 mmol), dichlorobis(tro-o-tolylphosphine)palladium(II)(0.101 g, 0.128 mmol), and potassium carbonate (0.531 g, 3.84 mmol) indioxane (20 mL) and water (1 mL) heated to 90° C. was addedphenylboronic acid (0.390 g, 3.20 mmol) and the reaction allowed to stirfor 1 h. The reaction was cooled to room temperature, filtered (celite),and the solvent removed in vacuo to provide a crude residue.Purification by flash column chromatography (silica, ethylacetate:hexanes 1:4) gave 0.422 g (85%) of2-[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dioneas a white solid. mp 163-166° C.

The following compounds were prepared generally according to theprocedure described for Intermediate 3:

Intermediate 4

2-{[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione:From2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2}1)-dioneand 2-fluorophenylboronic acid gave2-{[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(63%) as a white solid. mp 138-143° C.

Intermediate 5

2-{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione:From 2[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dioneand 2-chlorophenylboronic acid gave2-{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(69%) as a white solid. mp 153-158° C.

Intermediate 6

2-{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl)-1H-isoindole-1,3(2H)-dioneFrom2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dioneand 2-methylphenylboronic acid gave2-{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(62%) as a white solid. mp 163-167° C.

Intermediate 7

2-{[5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dioneFrom2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dioneand 2-methoxyphenylboronic acid gave2-{(5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl)-1H-isoindole-1,3(2H)-dione(63%) as a white solid. mp 149-153° C.

Intermediate 8

2-((5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)-1H-isoindole-1,3(2H)-dione:From 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione and2-(trifluoromethyl)phenylboronic acid gave2-((5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)-1H-isoindole-1,3(2H)-dione(60%) as a white solid. mp 160-163° C.

Example 1

[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine: To a suspension of2-[(7-phenyl-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione(0.382 g, 0.985 mmol) in ethanol (10 mL) was added the methylamine (33%in ethanol, 20 mL) and the reaction mixture was heated to 70° C. andallowed to stir for 1 h. The reaction mixture was allowed to cool toroom temperature and the solvent removed in vacuo. The residue wasdissolved in ethyl acetate (50 mL) and washed with water (2×20 mL),saturated aqueous sodium bicarbonate (20 mL), saturated aqueous sodiumchloride (20 mL), dried (magnesium sulfate), and the solvent removed invacuo. Purification by flash column chromatography (silica, 10% ammoniumhydroxide in methanol:ethyl acetate 1:9) provided a colorless oil thatwas dissolved in isopropanol (2 mL) and hydrogen chloride (1.0 N indiethyl ether, 5 mL) was added. The resulting precipitate was filtered,washed (diethylether), and dried to afford 0.165 g (57%) of[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine as a white solid.mp >225° C.

The following compounds were prepared generally according to theprocedure described for Example 1:

Example 2

{[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl]methyl}amine: From2-{[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dionegave {[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl]methyl}amine (25%)as a white solid. mp 218-223° C. (dec).

Example 3

{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}amine: From2-{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dionegave {[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}amine (32%)as a white solid. mp 247-250° C. (dec).

Example 4

{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}amine: From2-{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dionegave {[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}amine (33%)as a white solid. mp 219-222° C. (dec).

Example 5

{[5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}amine: From2-{[5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dionegave. {[5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}amine(36%) as a white solid. mp 228-231° C. (dec).

Example 6

({5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)amine: From2-({5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)-1H-isoindole-1,3(2H)-dionegave({5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)amine(20%) as a white solid. mp 215-218° C. (dec)

Example 7

{[7-(2,6-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl) amine: From2-[7-(2,6-dichloro-phenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave {[7-(2,6-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl}amine asa white solid. mp 213-215° C.

Example 8

{[5-fluoro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}amine: From2-(5-fluoro-7-(2-methylphenyl)-benzofuran-2-ylmethyl)-isoindole-1,3-dionegave {[5-fluoro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}amine as awhite solid. mp 193-194° C.

Example 9

{[7-(2,4-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl}amine: From2-[7-(2,4-dichlorophenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave {[7-(2,4-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl}amine asa white solid. mp 190° C. (dec).

Example 10

1-[5-fluoro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methanamine: From2-[5-fluoro-7-(2-methoxyphenyl)-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave 1-[5-fluoro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methanamine as awhite solid. mp 128-130° C.

Example 11

1-[7-(2,5-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methanamine: From2-[7-(2,5-dichlorophenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave 1-[7-(2,5-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methanamine asa white solid. mp 245-247° C.

Example 12

1-[7-(2-methylphenyl)-1-benzofuran-2-yl]methanamine: From2-(7-(2-methylphenyl)-1-benzofuran-2-ylmethyl)-isoindole-1,3-dione gave1-[7-(2-methylphenyl)-1-benzofuran-2-yl]methanamine as a white solid. mp222-224° C.

Example 13

1-[7-(4-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl]methanamine:From2-[7-(4-chloro-2-methylphenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave1-[7-(4-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl]methanamine asa white solid. mp 172-174° C.

Example 14

1-[7-(5-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl]methanamine:From2-[7-(5-chloro-2-methylphenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave1-[7-(5-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl]methanamine asa white solid. mp 208-210° C.

Example 15

1-[7-(2,6-dichlorophenyl)-1-benzofuran-2-yl]methanamine: From2-[7-(2,6-dichlorophenyl)-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave 1-[7-(2,6-dichlorophenyl)-1-benzofuran-2-yl]methanamine as a whitesolid. mp 260-262° C.

Example 16

1-[6-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methanamine: From2-[6-chloro-7-(2-chlorophenyl)-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave [6-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methanamine as awhite solid. mp 208-210° C.

Example 17

1-[7-(2-chlorophenyl)-6-fluoro-1-benzofuran-2-yl]methanamine: From2-[7-(2-chlorophenyl)-6-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dionegave 1-[7-(2-chlorophenyl)-6-fluoro-1-benzofuran-2-yl]methanamine as awhite solid. mp >250° C.

Biological Assays

The ability of the compounds of this invention to act as 5-HT_(2C)agonists and partial agonists was established using several standardpharmacological test procedures; the procedures used and resultsobtained are provided below. In the test procedures, 5-HT stands for5-hydroxytryptamine, mCPP stands for meta-chlorophenylpiperazine, andDOI stands for 1-(2,5-dimethoxy-4-iodophenyl)isopropylamine.

To evaluate the affinity of various compounds of formula I for activityat the 5-HT_(2C) receptor, a CHO (Chinese Hamster Ovary) cell linetransfected with the cDNA expressing the human 5-hydroxytryptamine-2C(h5-HT_(2C)) receptor was maintained in DMEM (Dulbecco's Modified EagleMedia) supplied with fetal calf serum, glutamine, and the markers:guaninephosphoribosyl transferase (GTP) and hypoxanthinethymidine (HT).The cells were allowed to grow to confluence in large culture disheswith intermediate changes of media and splitting. Upon reachingconfluence, the cells were harvested by scraping. The harvested cellswere suspended in half volume of fresh physiological phosphate bufferedsaline (PBS) solution and centrifuged at low speed (900×g). Thisoperation was repeated once. The collected cells were then homogenizedwith a polytron at setting #7 for 15 sec in ten volumes of 50 mMTris.HCl, pH 7.4 and 0.5 mM EDTA. The homogenate was centrifuged at900×g for 15 min to remove nuclear particles and other cell debris. Thepellet was discarded and the supernatant fluid recentrifuged at 40,000×gfor 30 min. The resulting pellet was resuspended in a small volume ofTris.HCl buffer and the tissue protein content was determined inaliquots of 10-25 μL volumes. Bovine Serum Albumin (BSA) was used as thestandard in the protein determination by the method of Lowry et al., (J.Biol. Chem., 193:265 (1951). The volume of the suspended cell membraneswas adjusted with 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid,10 mM pargyline and 4 mM CaCl₂ to give a tissue protein concentration of1-2 mg per ml of suspension. The preparation membrane suspension (manytimes concentrated) was aliquoted in 1 ml volumes and stored at −70 Cuntil used in subsequent binding experiments.

Binding measurements were performed in a 96 well microtiter plateformat, in a total volume of 200 μL. To each well was added: 60 μL ofincubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4mM CaCl₂; 20 μL of [¹²⁵I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).

The dissociation constant, KD of [¹²⁵I] DOI at the human serotonin5-HT_(2C) receptor was 0.4 nM by saturation binding with increasingconcentrations of [¹²⁵I] DOI. The reaction was initiated by the finaladdition of 100 μL of tissue suspension containing 50 μg of receptorprotein. Nonspecific binding is measured in the presence of 1 μMunlabeled DOI added in 20.0 μL volume. Test compounds were added in 20.0μL. The mixture was incubated at room temperature for 60 min. Theincubation was stopped by rapid filtration. The bound ligand-receptorcomplex was filtered off on a 96 well unifilter with a Packard®Filtermate 196 Harvester. The bound complex caught on the filter diskwas dried in a vacuum oven heated to 60° C. and the radioactivitymeasured by liquid scintillation with 40 μL Microscint-20 scintillant ina Packard TopCount® equipped with six (6) photomultiplier detectors.

Specific binding is defined as the total radioactivity bound less theamount bound in the presence of 1 μM unlabeled DOI. Binding in thepresence of varying concentrations of test drugs is expressed as percentof specific binding in the absence of drug. These results are thenplotted as log % bound vs log concentration of test drug. Non linearregression analysis of data points yields both the IC₅₀ and the K_(i)values of test compounds with 95% confidence limits. Alternatively, alinear regression line of decline of data points is plotted, from whichthe IC₅₀ value can be read off the curve and the K_(i) value determinedby solving the following equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L is the concentration of the radioactive ligand used and theK_(D) is the dissociation constant of the ligand for the receptor, bothexpressed in nM.

The following K_(i)'s (95% confidence interval) are provided for variousreference compounds in Table 2, below:

TABLE 2 K_(i) Data for Reference Compounds Compound K_(i) Ritanserin 2.0(1.3-3.1) nM Ketanserin 94.8 (70.7-127.0) nM Mianserin 2.7 (1.9-3.8) nMClozapine 23.2 (16.0-34.0) nM Methiothepin 4.6 (4.0-6.0) nM Methysergide6.3 (4.6-8.6) nM Loxapine 33.0 (24.0-47.0) nM mCPP 6.5 (4.8-9.0) nM DOI6.2 (4.9-8.0) nM

The ability of the compounds of formula I to produce an agonist responseat brain 5-HT_(2C) was assessed by determining their effect on calciummobilization using the following procedure: CHO cells stably expressingthe human 5-HT_(2C) receptor were cultured in Dulbecco's modifiedEagle's medium (DMEM) supplemented with 10% fetal bovine serum andnon-essential amino acids. Cells were plated at a density of 40Kcells/well in 96-well clear-bottom black-wall plates 24 hours prior tothe evaluation of 5-HT_(2C) receptor-stimulated calcium mobilization.For calcium studies, cells were loaded with the calcium indicator dyeFluo-3-AM in Hank's buffered saline (HBS) for 60 minutes at 37° C. Cellswere washed with HBS at room temperature and transferred to thefluorometric imaging plate reader (FLIPR, Molecular Devices, Sunnyvale,Calif.) for acquisition of calcium images. Excitation at 488 nm wasachieved with an Argon ion laser and a 510-560 nm emission filter wasused. Fluorescence images and relative intensities were captured at 1second intervals and cells were stimulated by addition of agonist after10 baseline measurements using the internal fluidics module of theFLIPR. An increase in fluorescence counts corresponds to an increase inintracellular calcium.

For the evaluation of agonist pharmacology the calcium changes inresponse to different concentrations of agonist were determined using amaximum minus minimum calculation of the raw fluorescence count data.Calcium changes were then expressed as a percentage of the responseobserved with a maximally effective concentration of 5-HT. EC₅₀ valueswere estimated by non-linear regression analysis of thelog-concentration % maximum 5-HT response curves using the 4-parameterlogistic function. In certain embodiments, compounds of the presentinvention provide an EC₅₀ of ≦about 1000 nM. In other embodiments,compounds of the present invention provide an EC₅₀ of ≦about 100 nM, inyet other embodiments ≦about 20 nM, in still other embodiments ≦about 5nM, and certain embodiments ≦about 2 nM.

The following EC₅₀'s are provided for various reference compounds inTable 3, below

TABLE 3 EC₅₀ Data for Reference Compounds: Compound EC₅₀ 5-HT 0.5 nM DOI0.5 nM mCPP 5.4 nM

Table 4 below shows the results of the activity of selected compounds ofthis invention in the assays described above. The compound numberscorrespond to the compound numbers in Table 1, supra. Compounds havingan activity designated as “A” provided a K_(i) value between 0.01 to 1nM; compounds having an activity designated as “B” provided a K_(i)value between 1 nM and 10 nM; and compounds having an activitydesignated as “C” provided a K_(i) value between 10 nM and 100 nM.Compounds having an activity designated as “D” provided an EC₅₀ value ofless than 10 nM; compounds having an activity designated as “E” provideda an EC₅₀ value between 10 nM and 200 nM; and compounds having anactivity designated as “F” provided a an EC₅₀ value between 200 nM and2000 nM.

TABLE 4 5-HT₂c Activity of Selected Compounds Compound 5-HT_(2C) Binding5-HT_(2C) Function Number K_(i) avg (nM) EC₅₀ (nM) EMax (%) 1 C F 70 2 BF 80 3 — D 100 4 — E 90 5 B E 90 6 C F 90 7 A D 100 8 B D 90 9 A D 90 10B E 80 11 A D 70 12 B D 70 13 B E 80 14 B E 80 15 A D 90 16 A D 90

The compounds of this invention thus have affinity for and agonist orpartial agonist activity at brain serotonin 5-HT_(2C) receptors. Theyare therefore of interest for the treatment of the central nervoussystem conditions described previously herein.

The entire disclosure of each patent, patent application, andpublication cited or described in this document is hereby incorporatedby reference.

While we have presented a number of embodiments of this invention, it isapparent that our basic construction can be altered to provide otherembodiments which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments which have been represented by way of example.

1-16. (canceled)
 17. A composition comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ andR^(1′) is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl; each of R², R³ and R⁴ is independentlyhydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN; Ar is thienyl, furyl, pyridyl, or phenylwherein Ar is optionally substituted with one or more R^(x) groups; eachR^(x) is independently halogen, —OH, —CN, lower alkyl, lower alkoxy,—CF₃, or —OCF₃; n is one or two; and one or more pharmaceuticallyacceptable carriers, further comprising an additional pharmaceuticalagent selected from an anti-psychotic agent, an antidepressive agent, ananti-obesity agent, an agent useful in the modulation of bladderactivity, an opioid antagonist, an agent for treating ADD or ADHD, acognitive improvement agent, an agent for treating sexual dysfunction,or a pain relieving agent.
 18. A method for treating a conditionselected from at least one of psychotic disorder, an anxiety disorder, abipolar disorder, a depressive disorder, premenstrual syndrome (PMS),premenstrual dysphoric disorder (PMDD), an eating disorder, a bladdercontrol disorder, substance abuse or substance dependence, a cognitiondisorder, ADD or ADHD, an impulsivity disorder, an addictive disorder,male or female sexual dysfunction, pain, a motion or motor disorder,Parkinson's disease epilepsy, migraine, chronic fatigue syndrome,anorexia nervosa, a sleep disorder, mutism, or one or more centralnervous system deficiencies in a patient, comprising administering tothe patient a therapeutically effective amount of a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ andR^(1′) is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl; each of R², R³ and R⁴ is independentlyhydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN; Ar is thienyl, furyl, pyridyl, or phenylwherein Ar is optionally substituted with one or more R^(x) groups; eachR^(x) is independently halogen, —OH, —CN, lower alkyl, lower alkoxy,—CF, or —OCF₃; n is one or two; or a composition comprising a compoundof Formula I, and one or more pharmaceutically acceptable carriers. 19.The method of claim 18 wherein the psychotic disorder is schizophrenia,paranoid type schizophrenia, disorganized type schizophrenia, catatonictype schizophrenia, undifferentiated type schizophrenia, aschizophreniform disorder, a schizoaffective disorder, a delusionaldisorder, substance-induced psychotic disorder, a psychotic disorder nototherwise specified; L-DOPA-induced psychosis; psychosis associated withAlzheimer's dementia; psychosis associated with Parkinson's disease; orpsychosis associated with Lewy body disease
 20. The method of claim 18,wherein the condition is bipolar disorder and is selected from bipolar Idisorder, bipolar II disorder, cyclothymic disorder; bipolar mania,dementia, depression with psychotic features, or cycling between bipolardepression and bipolar mania.
 21. The method of claim 18, wherein thedepressive disorder is major depressive disorder, seasonal affectivedisorder, dysthymic disorder, substance-induced mood disorder,depressive disorder not otherwise specified, treatment resistantdepression, major depressive episode.
 22. The method of claim 21,further comprising administering to the patient an antidepressive agentselected from serotonin reuptake inhibitors (SRIs), norepinephrinereuptake inhibitors (NRIs), combined serotonin-norepinephrine reuptakeinhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), reversibleinhibitors of monoamine oxidase (RIMAs), phosphodiesterase-4 (PDE4)inhibitors, corticotropin releasing factor (CRF) antagonists,alpha.-adrenoreceptor antagonists, triple uptake inhibitors, melatoninagonists, super neurotransmitter uptake blockers (SNUBs), noradrenergicand specific serotonergic antidepressants (NaSSAs), or substanceP/neurokinin receptor antagonists.
 23. The method of claim 18, whereinthe cognitive disorder is a learning disorder.
 24. The method of claim18, wherein the patient is treated for obesity.
 25. The method of claim18, wherein the patient is treated for ADD or ADHD.
 26. The method ofclaim 18, wherein the substance abuse substance dependence is of arecreational substance, a pharmacologic agent, a tranquilizer, astimulant, sedative, or illicit drug.
 27. The method of claim 18,further comprising administering to the patient an additionalpharmaceutical agent selected from an anti-psychotic agent, anantidepressive agent, an anti-obesity agent, an agent useful in themodulation of bladder activity, an opioid antagonist, an agent fortreating ADD or ADHD, a cognitive improvement agent, an agent fortreating sexual dysfunction, or a pain relieving agent.
 28. A method fortreating schizophrenia in a patient, comprising administering to thepatient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ andR^(1′) is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl; each of R², R³ and R⁴ is independentlyhydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN; Ar is thienyl, furyl, pyridyl, or phenylwherein Ar is optionally substituted with one or more R^(x) groups; eachR^(x) is independently halogen, —OH, —CN, lower alkyl, lower alkoxy,—CF, or —OCF₃; and n is one or two; or a composition comprising acompound of Formula I, and one or more pharmaceutically acceptablecarriers.
 29. A method for treating bipolar disorder in a patient,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ andR^(1′) is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl; each of R², R³ and R⁴ is independentlyhydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN; Ar is thienyl, furyl, pyridyl, or phenylwherein Ar is optionally substituted with one or more R^(x) groups; eachR^(x) is independently halogen, —OH, —CN, lower alkyl, lower alkoxy,—CF₃, or —OCF₃; and n is one or two; or a composition comprising acompound of Formula I, and one or more pharmaceutically acceptablecarriers.
 30. A method for treating depression in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each of R¹ andR^(1′) is independently hydrogen, methyl, ethyl, 2-fluoroethyl,2,2-difluoroethyl or cyclopropyl; each of R², R³ and R⁴ is independentlyhydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,trifluoromethoxy, or CN; Ar is thienyl, furyl, pyridyl, or phenylwherein Ar is optionally substituted with one or more R^(x) groups; eachR^(x) is independently halogen, —OH, —CN, lower alkyl, lower alkoxy,—CF₃, or —OCF₃; and n is one or two; or a composition comprising acompound of Formula I, and one or more pharmaceutically acceptablecarriers.